The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family. Activation of EGFR leads to homodimerization/heterodimerization, phosphorylation of specific tyrosine residues, and recruitment of several proteins at the intracellular portion of the receptors. In response, downstream signaling pathways, such as the Ras/Raf/MAPK pathway and/or the PI3K pathway may be activated, to further affect cellular targets, including nuclear activation of genes related with cell proliferation, survival, invasion, and metastasis. As such, Epidermal Growth Factor Receptor (EGFR) signaling pathways are involved in various proliferative conditions, in which the EGFR is abnormally activated. Various therapeutic agents which target these pathways are used in the treatment of various related disease, such as, lung cancer, colorectal cancer, head and neck cancer and pancreatic cancer. The therapeutic agents (inhibitors) include monoclonal antibodies (such as cetuximab, panitumumab), which are directed at the extracellular domain of the EGFR, and small-molecule tyrosine kinase inhibitors (such as gefitinib, erlotinib, lapatinib), which are competitive inhibitors of the receptor's tyrosine kinase.
The ability of EGFR inhibitors to block specific molecular pathways driving uncontrolled cellular division in cancer has resulted in a decreased incidence of serious systemic adverse events associated with chemotherapy. However, cutaneous adverse events to EGFR inhibitors have been reported, probably due to the abundant expression of EGFR in the skin and adnexal structures. Cutaneous adverse reactions to EGFR inhibitors include acneiform (papulopustular) rash, abnormal scalp, facial hair and/or eyelash growth, paronychia with or without pyogenic granulomas and telangiectasia.
BRaf is a signal transduction protein kinase involved in the regulation of the mitogen-activated protein kinase (MAPK or ERK) signaling pathway. Mutations in BRaf can induce constitutive signaling through the MAPK (MAPK) pathway which may result in uncontrolled cell proliferation. Use of BRaf inhibitors has been demonstrated to be associated with inhibition of MAPK signaling, as can be determined by inhibition or reduction in level of phosphorylated ERK, which is the downstream effector of BRaf. Yet, it has been further observed that paradoxically, BRaf inhibitors can induce an opposite effect of activation of MAPK signaling in BRaf wild-type cells (as determined by increased levels of phosphorylated ERK).
There is thus a need in the art for effective compositions that can be used to ameliorate or prevent the cutaneous adverse reaction of EGFR inhibitors or PI3K inhibitors in subjects treated with such inhibitors.